{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/ccb4bee2-16a6-4799-8548-6186508934f3/doc/sepio/version/1.0.0", "assertionMethod": { "@id": "https://cspec.genome.network/cspec/SequenceVariantInterpretation/id/135637578", "label": "ClinGen Phenylketonuria Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PAH Version 2.0.0", "type": "VariantPathogenicityInterpretationGuideline", "version": "2.0.0" }, "condition": { "@id": "https://api.monarchinitiative.org/api/bioentity/phenotype/MONDO:0009861", "id": "MONDO:0009861", "label": "phenylketonuria", "type": "GeneticCondition" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA16020921/MONDO:0009861/006/el/0/1831", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA16020921/MONDO:0009861/006/ei/1/1832", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50015_EP155190578201949", "id": "CG-PCER-AGENT:CG_50015_EP155190578201949", "type": "Agent" }, "contributionDate": { "date": "2026/3/1", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA16020921/MONDO:0009861/006/el/0/1831/1833", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA16020921/MONDO:0009861/006/ci/CA16020921/MONDO:0009861/006.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50015_EP155190578201949", "id": "CG-PCER-AGENT:CG_50015_EP155190578201949", "type": "Agent" }, "comments": "At least one patient with this variant displayed plasma phenylalanine concentration persistently above 120umol/L (2mg/dL) AND normal urine pterins and normal DHPR activity excluded a defect of BH4 cofactor metabolism, which is highly specific for PAH deficiency (PP4_Moderate, PMID 19394257). BH4 deficiency was excluded in all patients by measuring urinary pterins and dried blood dihydropteridine reductase activity.", "contributionDate": { "date": "2026/3/1", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "id": "CA16020921/MONDO:0009861/006/ci/CA16020921/MONDO:0009861/006.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA16020921/MONDO:0009861/006/0/1831/1833", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA16020921/MONDO:0009861/006/1/1832", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA16020921/MONDO:0009861/006/0/1831", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA16020921/MONDO:0009861/006/el/0/1753", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA16020921/MONDO:0009861/006/ei/1/1754", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50015_EP155190578201949", "id": "CG-PCER-AGENT:CG_50015_EP155190578201949", "type": "Agent" }, "contributionDate": { "date": "2026/3/1", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA16020921/MONDO:0009861/006/el/0/1753/1755", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA16020921/MONDO:0009861/006/ci/CA16020921/MONDO:0009861/006.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50015_EP155190578201949", "id": "CG-PCER-AGENT:CG_50015_EP155190578201949", "type": "Agent" }, "comments": "The computational predictor REVEL gives a score of 0.979, which meets the threshold of 0.932, evidence that correlates with strong impact to PAH function (PP3_Strong).", "contributionDate": { "date": "2026/3/1", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "id": "CA16020921/MONDO:0009861/006/ci/CA16020921/MONDO:0009861/006.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA16020921/MONDO:0009861/006/0/1753/1755", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA16020921/MONDO:0009861/006/1/1754", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA16020921/MONDO:0009861/006/0/1753", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA16020921/MONDO:0009861/006/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA16020921/MONDO:0009861/006/ei/1/1637", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50015_EP155190578201949", "id": "CG-PCER-AGENT:CG_50015_EP155190578201949", "type": "Agent" }, "contributionDate": { "date": "2026/3/1", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA16020921/MONDO:0009861/006/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA16020921/MONDO:0009861/006/ci/CA16020921/MONDO:0009861/006.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50015_EP155190578201949", "id": "CG-PCER-AGENT:CG_50015_EP155190578201949", "type": "Agent" }, "comments": "This variant is absent from gnomAD v4.1.0 (PM2_Supporting).", "contributionDate": { "date": "2026/3/1", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "id": "CA16020921/MONDO:0009861/006/ci/CA16020921/MONDO:0009861/006.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA16020921/MONDO:0009861/006/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA16020921/MONDO:0009861/006/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA16020921/MONDO:0009861/006/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA16020921/MONDO:0009861/006/el/0/1615", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA16020921/MONDO:0009861/006/ei/1/1616", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50015_EP155190578201949", "id": "CG-PCER-AGENT:CG_50015_EP155190578201949", "type": "Agent" }, "contributionDate": { "date": "2026/3/1", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA16020921/MONDO:0009861/006/el/0/1615/1617", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA16020921/MONDO:0009861/006/ci/CA16020921/MONDO:0009861/006.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50015_EP155190578201949", "id": "CG-PCER-AGENT:CG_50015_EP155190578201949", "type": "Agent" }, "comments": "Missense substitution of residues important in the active site architecture and/or substrate and/or cofactor binding of PAH: Gly346. Not applying since PP3 strong applies", "contributionDate": { "date": "2026/3/1", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "id": "CA16020921/MONDO:0009861/006/ci/CA16020921/MONDO:0009861/006.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA16020921/MONDO:0009861/006/0/1615/1617", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA16020921/MONDO:0009861/006/1/1616", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA16020921/MONDO:0009861/006/0/1615", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA16020921/MONDO:0009861/006/el/0/1717", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA16020921/MONDO:0009861/006/ei/1/1718", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50015_EP155190578201949", "id": "CG-PCER-AGENT:CG_50015_EP155190578201949", "type": "Agent" }, "contributionDate": { "date": "2026/3/1", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA16020921/MONDO:0009861/006/el/0/1717/1719", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA16020921/MONDO:0009861/006/ci/CA16020921/MONDO:0009861/006.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50015_EP155190578201949", "id": "CG-PCER-AGENT:CG_50015_EP155190578201949", "type": "Agent" }, "comments": "This variant has been detected in at least two individuals with Phenylketonuria. Of those individuals, one was compound heterozygous for the variant and a pathogenic variant (unknown phase), and one individual was homozygous for the variant (1 point, PMID: 32668217, PM3). genotype not reported in PMID: 19394257.", "contributionDate": { "date": "2026/3/1", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "id": "CA16020921/MONDO:0009861/006/ci/CA16020921/MONDO:0009861/006.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA16020921/MONDO:0009861/006/0/1717/1719", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA16020921/MONDO:0009861/006/1/1718", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA16020921/MONDO:0009861/006/0/1717", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA16020921/MONDO:0009861/006/el/0/1780", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA16020921/MONDO:0009861/006/ei/1/1781", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50015_EP155190578201949", "id": "CG-PCER-AGENT:CG_50015_EP155190578201949", "type": "Agent" }, "contributionDate": { "date": "2026/3/1", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA16020921/MONDO:0009861/006/el/0/1780/1782", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA16020921/MONDO:0009861/006/ci/CA16020921/MONDO:0009861/006.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50015_EP155190578201949", "id": "CG-PCER-AGENT:CG_50015_EP155190578201949", "type": "Agent" }, "comments": "Two missense variants, c.1036G>A (p.Gly346Arg) and c.1036G>C (p.Gly346Arg) [ClinVar Variation ID 102485, 102486], in the same codon have been classified as likely pathogenic for PAH deficiency by the ClinGen PAH Variant Curation Expert Panel [PM5]. Not applying to keep at LP, similar to other missense variants at this aa per PAH VCEP 2/18/26.", "contributionDate": { "date": "2026/3/1", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "id": "CA16020921/MONDO:0009861/006/ci/CA16020921/MONDO:0009861/006.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA16020921/MONDO:0009861/006/0/1780/1782", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA16020921/MONDO:0009861/006/1/1781", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA16020921/MONDO:0009861/006/0/1780", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA16020921/MONDO:0009861/006", "metadata": { "created": "2026-03-01T19:39:01.444Z", "note": "DISCLAIMER: While the data/content in this document is approved by ClinGen expert panel(s), the SEPIO schema presented here is an initial prototype and has not been reviewed nor finalized by the ClinGen Data Exchange Modeling Team. We expect it to differ significantly from the final schema.", "producedAtUTC": "Sun, 01 Mar 2026 19:39:01 -0000", "schemaLabel": "Evidence Repository.Beta-1 (Unofficial)", "version": "1.0.0" }, "statementOutcome": { "@id": "https://loinc.org/LA26332-9", "id": "LN:LA26332-9", "label": "Likely Pathogenic" }, "type": "VariantPathogenicityInterpretation", "uuid": "ccb4bee2-16a6-4799-8548-6186508934f3", "variant": { "@id": "https://reg.genome.network/allele/CA16020921", "id": "CAR:CA16020921", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000277.1:c.1037G>A" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000277.1:c.1037G>A" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-10-29T13:14:22.127Z" } }, "status": { "code": 200, "name": "OK" } }